This application is related to U.S. application Ser. No. 08/127,908, filed Sep. 28, 1993 which is a continuation-in-part of U.S. application Ser. No. 07/903,604, filed Jun. 24, 1992, which in turn is a continuation-in-part of U.S. application Ser. No. 07/708,936, filed May 31, 1991, which in turn is a continuation-in-part of U.S. application Ser. No. 07/638,185, filed Jan. 7, 1991, now abandoned.
The application also relates to U.S. application Ser. No. 08/127,980 filed Sep. 28, 1993 which is another continuation-in-part of U.S. patent application Ser. No. 07/903,604, U.S. patent application Ser. No. 08/077,359, filed Jun. 15, 1993, and to commonly assigned, co-pending U.S. patent application Ser. No. 07/903,525, filed Jun. 24, 1992 (a continuation-in-part of U.S. application Ser. No. 07/707,862, filed May 31, 1991, which in turn is a continuation in-part of U.S. application Ser. No. 07/638,743, filed Jan. 7, 1991, now abandoned) entitled xe2x80x9cEstrene Steroids as Neurochemical Initiators of Change in Human Hypothalamic Function and Related Pharmaceutical Compositions and Methodsxe2x80x9d; and to the commonly assigned, co-pending continuation-in-part of 07/903,525, U.S. patent application Ser. No. 08/077,140. The aforementioned U.S. patent applications are each incorporated herein by reference.
Finally, this application may relate to U.S. Patent Application entitled xe2x80x9cFragrance Compositions Containing Human Pheromones, filed Mar. 24, 1992, U.S. Ser. No. 07/856,435.
This invention relates generally to pharmaceutical compositions and methods for effectuating change in human hypothalamic function, thereby altering certain behavior and physiology mediated by the hypothalamus of individuals. More particularly, the invention relates to the use of 19-nor-cholane steroids as neurochemical effectuators of physiology and behavior.
The present invention relates to certain compounds, namely 19-nor-cholane steroids, particularly 19-nor-cholane steroids and related compounds as will be described herein, and methods of using these compounds as human vomeropherins in order to alter hypothalamic function, thereby affecting certain consequent behavior and physiology, e.g., the reduction of anxiety. The 19-nor-cholane steroids are characterized by a four ring steroidal structure, methylation at the 13 position and alkylation (C4) at the 17-position. The 19-nor-cholenes are a subset which have at least one double bond.
Ohloff, G. et al. (Helv. Chim. Acta (1983) 66:192-217), which is incorporated herein by reference, have shown that several steroids (androstenes) have an odor which varies with different isomeric, diastereomeric, and enantiomeric forms. Some members of this group have been reported to act as a pheromone in some mammalian species for instance, 5xcex1-androst-16-en-3-one and 5xcex1-androst-16-en-3xcex1-ol in pigs (Melrose, D. R., et al., Br. vet. J. (1971) 127:497-502). These 16-androstenes produced by the boar induce mating behavior in estrus sows (Claus, et al., Experimentia (1979) 35:1674-1675).
In some studies it has been noted that, in some species, various characteristics of certain 16-androstenes (including 5xcex1-Androst-16-en-3xcex1-ol and 5xcex1-Androst-16-en-3-one), such as concentration, metabolism, and localization, are sexually dimorphic (Brooksbank et al., J. Endocr. (1972) 52:239-251; Claus, et al., J. Endocr. (1976) 68:483-484; Rwan, et al., Med. Sci. Res. (1987) 15:1443-1444). For instance, 5xcex1-Androst-16-en-3xcex1-ol and 5xcex1-Androst-16-en-3-one, as well as Androsta-4,16-dien-3-one, have been found at different concentrations in the peripheral blood, saliva and axillary secretions of men and of women (Kwan, T. X., et al., Med. Sci. Res. (1987) 15:1443-1444), and their function as a human pheromone, to the extent of affecting choice and judgement, has been suggested (Id.; see also Gower, et al., xe2x80x9cThe Significance of Odorous Steroids in Axillary Odourxe2x80x9d, In, Perfumery, pp. 68-72, Van Toller and Dodd, Eds., Chapman and Hall, 1988); Kirk-Smith, D. A., et al., Res. Comm. Psychol. Psychiat. Behav. (1978) 3:379). Androstenol (5xcex1-androst-16-en-3xcex1-ol) has been claimed to exhibit a pheromone-like activity in a commercial men""s cologne and women""s perfume (Andron for men and Andron for women by Jovan). Japanese Kokai No. 2295916, refers to perfume compositions containing androstenol and/or its analogues. 5xcex1-Androstadien-3xcex2-ol (and perhaps the 3xcex1-ol) has also been identified in human axillary secretion (Gower, et al., Supra at 57-60. On the other hand, there is little agreement in the literature as to whether or not any putative pheromone actually plays any role in the sexual or reproductive behavior of mammals, particularly of humans. See: Beauchamp, G. X., et al., xe2x80x9cThe Pheromone Concept in Mammalian Chemical Communication: A Critiquexe2x80x9d, In: Mammalian Olfaction. Reproductive Processes and Behavior, Doty R. L., Ed., Academic Press, 1976). See also: Gower, et al., supra at 68-73.
The pheromone properties of some estrene steroids for some mammalian species have been described. Michael, R. P. et al., Nature (1968) 218:746 refers to Estrogens (particularly Estradiol) as a pheromonal attractant of male rhesus monkeys. Parrot, R. F., Hormones and Behavior (1976) 7:207-215, reports Estradiol benzoate injection induces mating behavior in ovariectomized rats; and the role of the blood level of Estradiol in make sexual response (Phoenix, C. H., Physiol. and Behavior (1976) 16:305-310) and female sexual response (Phoenix, C. H., Hormones and Behavior (1977) 8:356-362) in Rhesus monkeys has been described. On the other hand, there is little agreement in the literature as to whether or not pheromones as such play any role in the reproductive behavior and interpersonal communication of mammals (Beuchamp, G. K., et al., xe2x80x9cThe Pheromone Concept in Mammalian Chemical Communication: A Critiquexe2x80x9d, In: Mammalian Olfaction Reproductive Processes, and Behavior, Doty, R. L., Ed., Academic Press, 1976).
An embodiment of the subject invention concerns the non-systemic, nasal administration of certain 19-nor-cholane and 19-nor-cholene steroids to affect a specific behavioral or physiological response in human subjects, e.g., a reduction of negative affect, mood, and character traits. In particular, nasal administration provides for contacting neurochemical receptors of a heretofore poorly understood neuroendocrine structure, commonly known as the vomeronasal organ (xe2x80x9cVNO); also known as xe2x80x9cJacobson""s organxe2x80x9d), with one or more steroid(s) or with compositions containing the steroid(s). This organ is accessed through the nostrils of most higher animalsxe2x80x94from snakes to humans, and has been associated, inter alia, with pheromone reception in certain species (see generally Muller-Schwarze and Silverstein, Chemical Signals, Plenum Press, New York (1980)). The axons of the neuroepithelia of the vomeronasal organ, located supra palatinal, form the vomeronasal nerve and have direct synaptic connection to the accessory olfactory bulb and indirect input from there to the cortico-medial amygdaloid basal forebrain and hypothalamic nuclei of the brain. The distal axons of terminalis nerve neurons may also serve as neurochemical receptors in the VNO. Stensaas, L. J., et al., J. Steroid Biochem. and Molec. Biol. (1991) 39:553. This nerve has direct synaptic connection with the hypothalamus.
Johnson, A. et al. (J. Otolarynaoloav (1985) 14:71-79) report evidence for the presence of the vomeronasal organ in most adult humans, but conclude that the organ is probably non-functional. Contravening results which suggest that the VNO is a functional chemosensory receptor are reported by Stensaas, L., et al., supra; and by Moran, D. T., et al., Garcia-Velasco, J. and M. Mondragon; MontiBloch, L. and B. Grosser all in J. Steroid Biochem. and Molec. Biol. (1991) 39.
It is apparent that it would be desirable to identify and synthesize human vomeropherins and pheromones and to develop pharmaceutical compositions and methods of use to influence hypothalamic function. This invention relates to the unexpected discovery that, when nasally administered to human subjects, certain neurochemical ligands, particularly 19-nor-cholane steroids, 19-nor-cholene steroids and related compounds, or pharmaceutical compositions containing 19-nor-cholanes, 19-nor-cholenes or related compounds, specifically bind to chemoreceptors of certain nasal neuroepithelial cells and this binding generates a series of neurophysiological responses resulting in an alteration of hypothalamic function of an individual. When properly administered, the effect of certain of these compounds on the hypothalamus affects the function of the autonomic nervous system and a variety of behavioral- or physiological phenomena which include, but are not limited to the following: anxiety, premenstrual stress, fear, aggression, hunger, blood pressure, and other behavioral and physiological functions normally regulated by the hypothalamus. See Otto Appenzeller, The Autonomic Nervous System. An Introduction of Basic and Clinical Concepts (1990); Rorner, P. I. Central nervous control of autonomic cardiovascular function, and Levy N. M. and Martin, P. J. Neural control of the heart, both in Handbook of Physiology: Section 2: Cardiovascular Systemxe2x80x94the heart, Vol. I, Washington, D.C, 1979, American Physiological society; Fishman, A. P., et al. editors, Handbook of Physiology: Section 3: Respiratory System. Vol. II. Control of Breathing, Bethesda Md. 1986. American Physiological Society.
In some instances a single 19-nor-cholane steroid, or related compound, is administered, in some instances combinations of 19-nor-cholane steroids and/or related compounds are administered and in some instances one or more 19-nor-cholane steroids are coadministered along with one or more estrane or estrene steroids, androstane or androstene steroids or a related compound.
Definitions
An xe2x80x9caffectxe2x80x9d is a transient feeling state. Typical negative affects are feelings of nervousness, tenseness, shame, anxiousness, irritability, anger, rage, and the like. xe2x80x9cMoodsxe2x80x9d are longer lasting feeling states such as guilt, sadness, hopelessness, worthlessness, remorsefulness, misery, unhappiness and the like. xe2x80x9cCharacter traitsxe2x80x9d are more permanent aspects of an individual""s personality. Typical negative character traits are sensitivity, regretfulness, blameworthiness, stubbornness, resentfulness, bitterness, timidness, laziness and the like.
xe2x80x9c19-nor-cholane steroidsxe2x80x9d are aliphatic polycyclic hydrocarbons characterized by a four-ring steroidal structure with a methylation at the 13-position and alkylation (C4 or higher) (including unsaturated groups) at the 17-position. The 19-nor compounds lack a methyl or other carbon-containing substituent on C-10 where C-19 would normally be found. A cholene is a subset of cholanes commonly understood to mean that the compound has at least one double bond.
A xe2x80x9cchemoreceptorxe2x80x9d is a receptor molecule displayed on the surface of a xe2x80x9cchemosensoryxe2x80x9d neuroepithelial cell which binds in a stereospecific fashion to a particular ligand or ligands. This specific binding initiates a signal transduction which initiates an afferent nerve impulse. Chemoreceptors are found, inter alia, in taste buds, olfactory epithelium and vomeronasal tissue.
xe2x80x9c19-nor-cholene steroidsxe2x80x9d, as the term is used herein, are aliphatic polycyclic hydrocarbons with a four-ring steroidal structure, at least one double bond in the A-ring, methylation at the 13-position, alkylation (C4 or higher) (including unsaturated groups) at the 17-position and an oxo, hydroxyl or hydroxyl derivative such as an alkoxy, ester, benzoate, cypionate, sulfate or glucuronide, at the 3-position. The 19-nor compounds lack a methyl or other carbon-container substituent or C-10 where C-19 would normally be found.
The following structure shows the four-ring steroidal structure common to cholane and cholene steroids. In describing the location of groups and substituents, the following numbering system will be employed: 
xe2x80x9cSexually dimorphicxe2x80x9d refers to a difference in the effect of, or response to, a pharmaceutical agent between males and females of the same species.
An xe2x80x9ceffective amountxe2x80x9d of a drug is a range of quantity and/or concentration which brings about a desired physiological and/or psychological effect when administered to an individual in need of the drug. In the present case, a needy individual is one with a physiological or behavioral trait which is normally regulated by the hypothalamus and wherein it is desirable to affect the function of the hypothalamus or the trait. The effective amount of a given drug may vary depending upon the function to be affected, the desired effect, route of administration, and the like. For example, when the steroid in administered as a solution applied to the facial skin of a subject an effective concentration is from 1 microgram/ml to 100 xcexcg/ml, preferably 10 to 50 xcexcg/ml and most preferably 20 to 30 xcexcg/ml. When the steroid is introduced directly into the VNo an effective amount is about 1 picogram to about 1 nanogram, more preferably about 10 picograms to about 50 picograms. When the steroid is administered to the nasal passage, by ointment, cream or aerosol, or the like, an effective amount is about 100 pg to about 100 micrograms, preferably about 1 ng to about 10 micrograms. It follows that some drugs may be effective when administered by some routes, but not effective when administered by other routes.
The xe2x80x9chypothalamusxe2x80x9d is the portion of the diencephalon comprising the ventral wall of the third ventricle below the hypothalamic sulcus and including structures forming the ventricle floor, including the optic chiasma, tuber cinereum, infundibulum, and mammillary bodies. The hypothalamus regulates the autonomic nervous system and controls several physiological and behavioral functions such as the so-called fight and flight responses, sexual motivation, water balance, sugar and fat metabolism, hunger, regulation of body temperature, endocrine secretions, and others. The hypothalamus is also the source of vasopressin which regulates blood pressure, and oxytocin which induces parturition and milk release. All hypothalamic functions are potentially modulatable by the vomeropherin therapy described herein.
A xe2x80x9cligandxe2x80x9d, as used herein, is a molecule which acts as a chemical signal by specifically binding to a receptor molecule displayed on the surface of a receptor cell, thereby initiating a signal transduction across the cell surface. Binding of ligands to chemosensory receptors can be measured. Chemosensory tissue, such as vomeronasal neuroepithelium or olfactory neuroepithelium, contains a multiplicity of neuroreceptors cells, each displaying at least one cell surface receptor. Many of the receptor molecules have identical ligand specificity. Therefore, when the tissue is exposed to a ligand for which it has specificity (for example a exposure of the VNO to a vomeropherin) a summated change in cell surface receptor potential can be measured.
As used herein, xe2x80x9clower alkylxe2x80x9d means a branched or unbranched saturated hydrocarbon chain of 1 to 4 carbons, such as, for example, methyl, ethyl, n-propyl, i-butyl and the like. xe2x80x9cAlkoxyxe2x80x9d as used herein is used in its conventional sense to mean the group xe2x80x94OR wherein R is alkyl as herein defined.
A xe2x80x9cpheromonexe2x80x9d is a substance that provides chemical means of communication between members of the same species through secretion and peripheral chemoreception. In mammals pheromones are usually detected by receptors in the vomeronasal organ of the nose. Commonly, pheromones effect development, reproduction and related behaviors. A xe2x80x9cvomeropherinxe2x80x9d is a more general term which includes pheromones and describes a substance from any source which functions as a chemosensory messenger, binds to a specific vomeronasal neuroepithelial receptor, and induces a physiological or behavioral effect. The physiologic effect of a xe2x80x9cvomeropherinxe2x80x9d is mediated through the vomeronasal organ.
A picogram (pg) is equal to 0.001 nanograms (ng). A ng is equal to 0.001 micrograms (xcexcg). A xcexcg is equal to 0.001 mg.
The invention is directed to a group of certain 19-nor cholane steroids.
A subset of 19-nor-cholanes within the group are believed to be novel. Syntheses are described herein for certain compounds in the Schemes.